Substituted phenols as novel calcium channel blockers

ABSTRACT

The present invention relates to novel substituted phenols and derivatives thereof useful in the treatment of neurological disorders. Methods of preparing the compounds, intermediates useful in the preparation and pharmaceutical compositions containing the compounds are also includes.

This application is the national phase of PCT/US96/08064, filed Jul. 16,1996, now WO 97/05126, which claims priority to provisional applicationNo. 60/001,662 filed Jul. 27, 1995.

The present invention relates to novel substitutedbis-(4-hydroxyphenyl)methanes and derivatives thereof useful aspharmaceutical agents, to methods of their production, compositionswhich include these compounds and a pharmaceutically acceptable carrier,and to pharmaceutical methods of treatment. The novel compounds of thepresent invention are useful in the treatment of neurological disorderssuch as traumatic brain injury, cerebral ischemia, stroke, migraine,acute and chronic pain, epilepsy, Parkinson's disease, Alzheimer'sdisease, amyotropic lateral sclerosis, multiple sclerosis, anddepression. The compounds may also be useful for the treatment ofnonneurological disorders such as asthma.

The entry of excessive amounts of calcium ion into neurons following anischemic episode or other neuronal trauma has been well documented.Uncontrolled high concentrations of calcium in neurons initiates acascade of biochemical events that disrupt normal cellular processes.Among these events are the activation of proteases and lipases,breakdown of neuronal membranes and the formation of free radicals whichmay ultimately lead to cell death. In particular, the selective N-typecalcium channel blocker, SNX-111, has demonstrated activity in a numberof models of ischemia and pain (Bowersox S. S., et al., Drug News andPerspective, 1994; 7:261-268 and references cited therein).

Therefore, compounds which block N-type calcium channels may be usefulin the treatment of neurological disorders such as traumatic braininjury, stroke, migraine, acute and chronic pain, epilepsy, Parkinson'sdisease, Alzheimer's disease, amyotrophic lateral sclerosis, multiplesclerosis, and depression.

SUMMARY OF THE INVENTION

A compound of formula ##STR1## wherein R¹ to R¹¹, X, Y, m, n, and o areas defined below are useful in treating various neurological disordersand nonneurological disorders such as asthma.

Preferred compounds of the invention are those of formula ##STR2##wherein R¹, R², R⁴, R⁶, R⁸, R⁹, R¹⁰, X, Y, m, n, and o are as definedbelow, and ##STR3## wherein R¹, R², R⁴, R⁶, R⁸, R⁹, R¹⁰, X, Y, and m areas defined below.

Still more preferred compounds are those of Formula III wherein R¹, R²,R⁴, R⁶, R⁸, R⁹, R¹⁰, Y, and m are as defined below and X is --(CH₂)_(p)-- or --(CH₂)_(p) ##STR4##

The most preferred compounds are selected from

4,4'-(4-Hydroxy-1-methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol],

4,4'-(1Methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol],

4,4'-[4-[Bis(phenylmethyl)amino]-1-methyl-butylidene]bis[2-[(hexahydro-1H-azepin-1yl)methyl]phenol],

N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]benzamide,

N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-2,2-diphenylacetamide,and

N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)-1-methylethyl]benzamide.

Other aspects of the instant invention are methods of treatingneurological disorders such as: traumatic brain injury, cerebralischemia, acute and chronic pain, epilepsy, Parkinsonism, Alzheimer'sdisease, amyotrophic lateral sclerosis, multiple sclerosis, anddepression. Other disorders such as asthma are also treated.

DETAILED DESCRIPTION

The compounds of the instant invention are those of Formula I ##STR5##or a pharmaceutically acceptable salt thereof wherein: R¹ and R² areeach independently hydrogen, alkyl, aryl or arylalkyl, or may be takentogether with the nitrogen to which they are attached to form a ring offrom 4 to 8 carbon atoms, --CH₂ CH₂ OCH₂ CH₂ --, or --CH₂ CH₂ SCH₂ CH₂--;

R⁸ and R⁹ are each independently hydrogen, alkyl, aryl or arylalkyl, ormay be taken together with the nitrogen to which they are attached toform a ring of from 4 to 8 carbon atoms, --CH₂ CH₂ OCH₂ CH₂ --, or --CH₂CH₂ SCH₂ CH₂ --;

R³, R⁴, R⁵, R⁶, R⁷, R¹⁰, and R¹¹ are each independently hydrogen, alkyl,or halogen;

X is --(CH₂)_(p),

--(CH₂)_(p) CONR¹⁶ --,

--(CR¹⁸ R¹⁹)_(p) NR¹⁶ CO--, wherein each R¹⁸ and R¹⁹ is eachindependently hydrogen or alkyl of from 1 to 4,

--(CH₂)_(p) NR¹⁶ --,

--(CH₂)_(p) O--,

--(CH₂)_(p) S--, wherein p is an integer from 0 to 3 and R¹⁶ is hydrogenor alkyl;

Y is NR¹² R¹³, CR¹⁷ R¹² R¹³, aryl, or heteroaryl wherein R¹⁷ ishydrogen, hydroxy, or alkyl;

R¹² and R¹³ are each independently hydrogen, alkyl, aryl, arylalkyl,heteroaryl, or heteroarylalkyl;

n is an integer from 1 to 3;

o is an integer from 1 to 3; and

m is an integer from 0 to 3.

In the compounds of the present invention, the term alkyl, in generaland unless specifically limited, means a straight, branched, or cyclicalkyl group of from 1 to 7 carbon atoms including but not limited tomethyl, ethyl, propyl, isopropyl, butyl, isobutyl, cyclopentyl, andcyclohexyl.

Aryl refers to a mono- or polycyclic carbocyclic aromatic ring, forexample, but not limited to, phenyl and naphthyl. The aryl group may beunsubstituted or substituted by one or more substituents selected fromsimple alkyl, halogen OH, OCH₃, NO₂, and NHCOCH₃.

Arylalkyl is defined as above in the term alkyl and aryl as is, forexample, and not limited to benzyl, 2-phenylethyl, and 3-phenylpropyl.

Heteroaryl is a mono- or polycyclic aromatic ring which contains aheteroatom, for example, but not limited to furanyl, thienyl, andisoquinolinyl.

Heteroarylalkyl is defined as above in the term alkyl and heteroaryl,for example, but not limited to 2-(2-thienyl)ethyl, 2-thienylmethyl,2-pyridylmethyl, and the like.

Halogen is fluorine, chlorine, bromine, or iodine; fluorine, chlorine,and bromine are preferred.

Carbocyclic ring is a 5- to 7-membered saturated or unsaturated ring andincludes, for example, but not limited to cyclopentane, cyclopentene,cyclohexane, cyclohexene, cycloheptane, cycloheptene, indane, andtetralin.

The compounds of Formula I are capable of further forming bothpharmaceutically acceptable acid addition and/or base salts. All ofthese forms are within the scope of the present invention.

Pharmaceutically acceptable acid addition salts of the compounds ofFormula I include salts derived from nontoxic inorganic acids such ashydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydriodic,hydrofluoric, phosphorous, and the like, as well as the salts derivedfrom nontoxic organic acids, such as aliphatic mono-, di-, andtricarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. Such salts thus include sulfate, pyrosulfate,bisulfate, sulfite, bisulfite, nitrate, phosphate,monohydrogenphosphate, dihydrogenphosphate, metaphosphate,pyrophosphate, chloride, bromide, iodide, acetate, trifluoroacetate,propionate, caprylate, isobutyrate, oxalate, malonate, succinate,suberate, sebacate, fumarate, maleate, mandelate, benzoate,chlorobenzoate, methylbenzoate, dinitrobenzoate, phthalate,benzenesulfonate, toluenesulfonate, phenylacetate, citrate, lactate,maleate, tartrate, methanesulfonate, and the like. Also contemplated aresalts of amino acids such as arginate and the like and gluconate,galacturonate (see, for example, Berge S. M., et al., "PharmaceuticalSalts, " J. of Pharma. Sci., 1977; 66:1).

The acid addition salts of said basic compounds are prepared bycontacting the free base form with a sufficient amount of the desiredacid to produce the salt in the conventional manner. Preferably, acompound of Formula I can be converted to an acidic salt by treatingwith an aqueous solution of the desired acid, such that the resulting pHis less than four. The free base form may be regenerated by contactingthe salt form with a base and isolating the free base in theconventional manner. The free base forms differ from their respectivesalt forms somewhat in certain physical properties such as solubility inpolar solvents, but otherwise the salts are equivalent to theirrespective free base for purposes of the present invention.

Pharmaceutically acceptable base addition salts are formed with metalsor amines, such as alkali and alkaline earth metals or organic amines.Examples of metals used as cations are sodium, potassium, magnesium,calcium, and the like. Examples of suitable amines areN,N'-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine,dicyclohexylamine, ethylenediamine, N-methylglucamine, and procaine(see, for example, Berge S. M., et al., "Pharmaceutical Salts," J. ofPharma. Sci., 1977; 66:1).

The base addition salts of said acidic compounds are prepared bycontacting the free acid form with a sufficient amount of the desiredbase to produce the salt in the conventional manner. Preferably, acompound of Formula I can be converted to a base salt by treating withan aqueous solution of the desired base, such that the resulting pH isgreater than nine. The free acid form may be regenerated by contactingthe salt form with an acid and isolating the free acid in theconventional manner. The free acid forms differ from their respectivesalt forms somewhat in certain physical properties such as solubility inpolar solvents, but otherwise the salts are equivalent to theirrespective free acid for purposes of the present invention.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R or S configuration.The present invention includes all enantiomeric and epimeric forms aswell as the appropriate mixtures thereof.

BIOLOGICAL ACTIVITY

The compounds of the invention exhibit valuable biological propertiesbecause of their ability to potently block calcium flux through N-typevoltage gated calcium channels. To measure interaction at the N-typecalcium channel and calcium flux inhibition, the effects of the calciumchannel blockers were measured in the assays described below.

Chick Whole Brain Synaptosomal ⁴⁵ Calcium Flux Assay

Chicken brain synaptosomes contain voltage sensitive calcium channelswhich are inhibited by nanomolar concentrations of ω-contoxins and aretherefore considered to be primarily N-type (Lundy P. M., Hamilton M.G., Frew R., Brain Res., 1994; 643:204-210). ⁴⁵ Ca flux into thesynaptosomes may be induced by stimulation of the synaptosomal membranewith elevated potassium concentrations. A compound is assessed atvarious concentrations for its ability to inhibit this potassiumstimulated calcium influx.

Methods

One- to five-week old chicks were killed by decapitation and whole brainwas removed. The brainstem was discarded, and the remaining brain tissuewas placed in ice-cold sucrose buffer (composition: 320 mM sucrose, 5.0mM TRIS base, 0.1 mM EDTA, pH adjusted to 7.3 with HCl). The total wetweight of pooled brain tissue was determined, and the tissue washomogenized in 10 mL sucrose buffer per gram wet weight. A Potter S-typehomogenizer (B. Braun Co.) with a glass tube and teflon pestle was used.Five strokes at 400 rpm were followed by four strokes at 800 rpm. Thehomogenate was poured into cold centrifuge tubes and centrifuged for 10minutes at 3000 rpm (1,075 g) in a refrigerated 4° C. RC-5 centrifuge(Sorvall) using an SS-34 rotor. The supernatant was collected andcentrifuged at 11,500 rpm (15,800 g) for 10 minutes. The supernatant wasdiscarded, and the pellet was resuspended in 1 mL sucrose buffer. Coldincubation buffer (composition: 1.2 mM MgCl₂, 22 mM HEPES, 11 mMglucose, 3 mM KCl, 136 mM choline chloride, pH adjusted to 7.3 with TRISbase) was added slowly to the suspension for a total volume of 30 to 40mL. This mixture was centrifuged at 7,000 rpm (5,856 g) for 5 minutes.The supernatant was discarded, and the pellet was resuspended in 5 mL ofincubation buffer per gram of original wet weight of brain. Thissynaptosomal suspension was kept on ice until the start of the assay, atwhich time 35 μL of synaptosome suspension were added to each well of a96-well filter plate (Millipore) which contained 75 μL incubation bufferwith or without drug. Drugs were dissolved in DMSO or H₂ O, and theconcentration of DMSO was less than or equal to 1%.

Synaptosomes were pre-incubated in the presence or absence of drug for 5minutes at room temperature before the addition of radioactive calcium.Drugs were present throughout the assay. Two μCi/mL stocks of ⁴⁵ CaCl₂were prepared in basal buffer (composition: incubation buffer plus 1 mMCaCl₂) and in stimulation buffer (composition: 1.2 mM MgCl₂, 22 mMHEPES, 11 mM glucose, 37 mM KCl, 102 mM choline chloride, 1 mM CaCl₂, pHadjusted to 7.3 with TRIS base). One hundred microliter of radioactivebasal or stimulation buffer were pipetted into a pre-incubated plate ofsynaptosomes using a Quadra 96 pipetter (Tomtec). The final KClconcentration was 3 mM for the basal condition and 20 mM for thestimulated condition; the final CaCl₂ concentration was 0.5 mM with 1μCi/mL of ⁴⁵ CaCl₂. The plate was filtered under vacuum after a30-second incubation with radioactivity. The filters were washed twicewith 200 μL of wash buffer (composition: 140 mM choline chloride, 3 mMEGTA, 22 mM HEPES, pH adjusted to 7.3 with TRIS base). Plates wereallowed to dry completely. Scintillation fluid was added (20 μL/well),and the plates were counted in a Wallace Microbeta plate counter. Basal⁴⁵ CaCl₂ flux (3 mM KCl) was subtracted from stimulated ⁴⁵ CaCl₂ flux(20 mM KCl) in both control and drug-treated conditions, and data wereexpressed as percent inhibition of the adjusted control response. Valuesobtained in this way were plotted as a function of drug concentrationand IC₅₀ values were calculated.

Measurement of N-type Ca2+ Channel Blocking Potencies of Compounds inIMR-32 Cells Using the Fluorescent Ca2+ Indicator Indo-1

IMR-2 cells are a human tumoral cell line of neural origin. The IMR-32cell line has been shown to contain both N- and L-type voltage sensitivecalcium channels. Calcium flux into these cells may be induced bystimulation with elevated potassium concentrations. The L-channelcomponent of calcium flux may be blocked by adding 5 μM nitrendipine.The remaining component of calcium entry into the IMR-32 cells is due tocalcium flux through N-type calcium channels. Intracellular calciumconcentrations are measured using the fluorescent calcium indicatorIndo-1. The effect of drug concentration on calcium uptake is studied.

Methods

The IMR-32 cell line was obtained from the American Type CultureCollection (Rockville, Md.). Cells were grown in Eagle's MinimumEssential Medium with Earle's salts supplemented with 10% fetal bovineserum, 2 mM L-Gln and antibiotic/antimicotic mixture (Gibco). Atapproximately 80% confluency, differentiation was induced by theaddition of 1 mM dibutyryl cAMP and 2.5 μM bromodeoxyuridine to themedium. After 7 to 13 days of differentiation, cells were detached using0.5 mM EDTA and loaded with 5 μM Indo-1 acetoxymethyl ester (MolecularProbes, Eugene, Or.) at 30° C. for 45 minutes. Loaded cells were washedtwice, resuspended (˜10⁷ cells/mL) in assay buffer (10 mM HEPES/Tris pH7.4 in Hank's Balanced Salt Solution without bicarbonate or phenol redcontaining 0.5% bovine serum albumin) and kept on ice until use.Fluorescence measurements were carried out in a Photon TechnologyInternational (PTI, South Brunswick, N.J.) Model RF-F3004spectrofluorometer with dual emission monochromators using excitation at350 nm and emission at 400 and 490 nm. The instrument was equipped witha thermostatted cuvette holder with stirring capabilities as well aswith a computer-controlled pump which allowed for reagent additionduring measurement. Instrument control and data collection was done byPTI's OSCAR software running on an IBM compatible computer. Differentconcentrations of the test compounds (60 μL in dimethyl sulfoxide) wereadded to 5.94 mL of assay buffer containing approximately 3×10⁶ loadedcells, and 5 μM Nitrendipine (in 30 μL EtOH) to block L-type Ca²⁺channels. Samples were incubated for 10 minutes at 30° C. and thenaliquoted into three 10×10 mm disposable acrylic cuvettes. Emissionsignals at 400 and 490 nm were acquired from each cuvette at 30° C. for50 seconds. At 20 seconds after the start of reading, cells weredepolarized by the addition of 160 μL of stimulation solution (1M KCl,68 mM CaCl₂) to the cuvette via the computer-controlled pump. Ratio ofdual emission signals (400 nm/490 nm), which is proportional tointracellular Ca²⁺ concentration, was plotted against time, and thedifference between maximal response after stimulation and basal value(before stimulation) was determined. Values obtained in this way wereplotted as a function of drug concentration. IC₅₀ values of testcompounds were calculated by fitting a 4-parameter logistic function tothe data using the least squares method.

                  TABLE 1                                                         ______________________________________                                        Inhibition of Calcium Flux in Chicken                                         Synaptosomes and IMR-32 Cells                                                            Inhibition of .sup.45 Ca.sup.+2                                                             Inhibition of .sup.45 Ca.sup.+2                      Example    Influx in Chick                                                                             Influx in IMR-32                                     No.        Synaptosomes IC.sub.50 μM                                                                Cells IC.sub.50 μM                                ______________________________________                                         3         1.40          0.49                                                  6         3.15          0.74                                                 10         4.20          0.43                                                 19         2.40          17.0                                                 20         2.40          1.80                                                 21         2.20          14.0                                                 ______________________________________                                    

Table 1 above summarizes the findings of the two assays.

The claimed compounds generally inhibited calcium influx into chickensynaptosomes and IMR-32 cells with IC₅₀ s of less than 20 μM.

The following nonlimiting examples illustrate the present invention.

EXAMPLE 1 ##STR6##4,4'-(4-Hydroxy-1-methyl-4,4-diphenylbutylidene)-bisphenol

A solution of 4,4-bis(4-hydroxyphenyl)pentanoic acid methyl ester (4.58g, 15.3 mmol) in 100 mL of anhydrous tetrahydrofuran was cooled to 0° C.and treated dropwise with phenylmagnesium bromide (10 mL of a 3Msolution in ether). Additional tetrahydrofuran (50 mL) was added to thereaction mixture followed by phenylmagnesium bromide (10.4 mL of a 3Msolution in ether). The reaction was warmed to room temperature andstirred for 3 hours. The reaction was cooled to 0° C. and treated withphenylmagnesium bromide (10.2 mL of a 3M solution in ether). Thereaction mixture was warmed to room temperature and stirred for 18hours. The reaction mixture was cooled to 0° C. and treated withsaturated aqueous NH₄ Cl solution (100 mL). The organic phase wascollected and the aqueous phase was extracted with ethyl acetate (3×100mL). The combined organic extracts were dried (MgSO₄), filtered andconcentrated. The residue was purified by chromatography (silica gel,40% ethyl acetate/hexanes) to give the title compound (6.22 g, 96%) as awhite solid.

EXAMPLE 2 ##STR7##4,4'-(4-Hydroxy-1-methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol]

A solution of the compound from Example 1 (1.01 g, 2.36 mmol),hexamethyleneimine (0.53 mL, 4.70 mmol) and 37% aqueous formaldehyde(0.36 mL, 4.80 mmol) in 40 mL of ethanol was heated at 50° C. undernitrogen atmosphere for 72 hours. Additional hexamethyleneimine (0.27mL, 2.35 mmol) and 37% aqueous formaldehyde (0.18 mL, 2.40 mmol) wasadded and the reaction mixture heated at 50° C. for 48 hours. Thereaction mixture was cooled and concentrated. The residue was dissolvedin ethyl acetate (50 mL) and washed with brine (30 mL). The organicphase was dried (MgSO₄), filtered, and concentrate. The residue waspurified by chromatography (silica gel, 75% ethyl acetate/hexane) togive the title compound.

EXAMPLE 3 ##STR8##4,4'-(4-Hydroxy-1-methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol]oxalic acid salt

A solution of the compound from Example 2 (0.27 g, 0.42 mmol) in 6 mL ofether was treated with oxalic acid (0.106 g, 0.84 mmol) in 1 mL ofethanol. The white precipitate which formed was collected and washedwith 20 mL of ether. The solid obtained was dried under vacuum (P₂ O₅)to give the title compound as a white solid, mp=135-150° C.

Analysis calculated for C₄₃ H₅₄ N₂ O₃.2.26 C₂ H₂ O₄ :

C, 67.12; H, 6.94; N, 3.30.

Found: C, 67.12; H, 7.16; N, 3.24

EXAMPLE 4 ##STR9## 4,4'-(1-Methyl-4,4-diphenylbutylidene)bisphenol

A solution of the product from Example 1 (2.00 g, 4.71 mmol) in 100 mLof methanol was shaken with 20% Pd/C (0.25 g) on a Parr apparatus undera H₂ atmosphere (50 psi) for 21 hours. The reaction mixture was filteredand the filtrate concentrated to give the title compound (1.64 g, 85%)as a white foam.

EXAMPLE 5 ##STR10##4,4'-(1-Methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol]

A solution of the product from Example 4 (0.75 g, 1.84 mmol),hexamethyleneimine (0.42 mL, 3.68 mmol) in 30 mL of ethanol was heatedat 50° C. under a N₂ atmosphere for 48 hours. The reaction mixture wasconcentrated and the residue was dissolved in ethyl acetate (75 mL) andwashed with brine (30 mL). The combined organic extracts were dried(MgSO₄), filtered and concentrated to give the title compound (0.23 g,20%) as an oil.

EXAMPLE 6 ##STR11##4,4'-(1-Methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol]oxalic acid salt

The product from Example 5 (0.14 g, 0.22 mmol) was dissolved in 5 mLether and treated with a solution of oxalic acid (0.564 g, 0.45 mmol) in1 mL ethanol. The precipitate which formed was collected by filtrationthe washed with ether. The white solid obtained was dried under vacuum(P₂ O₅) to give the title compound (0.16 g, 90%), mp=128-164° C.

Analysis calculated for C₄₃ H₅₄ N₂ O₂.2.0 C₂ H₂ O₄ :

C, 69.61; H, 7.21; N, 3.45.

Found: C, 70.00; H, 7.21; N, 3.32.

EXAMPLE 7 ##STR12## 4,4-Bis-(4-hydroxyphenyl)pentanoic aciddibenzylamide

A solution of 4,4-bis-(4-hydroxyphenyl)pentanoic acid (2.00 g, 6.99mmol) in 40 mL anhydrous tetrahydrofuran was treated with carbonyldiimidazole (3.76 g, 23.2 mmol) and the resulting solution heated atreflux under a N₂ atmosphere for 24 hours. Dibenzylamine (5.38 mL, 28mmol) was then added, and the reaction refluxed again for 48 hours. Thereaction mixture was cooled and treated with 10% aqueous HCl solution(50 mL), followed by water (100 mL) and ethyl acetate (200 mL). Theorganic phase was collected and washed sequentially with water (100 mL)and brine (100 mL). The organic phase was dried (MgSO₄), filtered andconcentrate. The residue was purified by chromatography (silica gel, 50%ethyl acetate/hexane) to give the title compound (1.30 g, 40%) as asolid, mp=203-207° C.

Analysis calculated for C₃₁ H₃₁ NO₃ :

C, 79.97; H, 6.71; N, 3.01.

Found: C, 79.71; H, 6.78; N, 2.87.

EXAMPLE 8 ##STR13##4,4'-[4-[Bis(phenylmethyl)amino]-1-methylbutylidene]-bisphenol

A solution of the product from Example 7 (1.00 g, 2.15 mmol) in 25 mL ofanhydrous tetrahydrofuran (THF) was treated dropwise with lithiumaluminum hydride solution (4.3 mL of a 1M solution in THF). Theresulting solution was heated at reflux for 18 hours. The reaction wascooled and quenched by the addition of saturated NH₄ Cl solution andextracted with THF. The combined organic extracts were washed withsaturated NaCl solution. The organic phase was dried (MgSO₄), filtered,and concentrated to give the title compound (1.03 g, 100%) as a whitefoam.

EXAMPLE 9 ##STR14##4,4'-[4-[Bis(phenylmethyl)amino]-1-methylbutylidene]-bis[2-[(hexahydro-1H-azepin-1yl)methyl]phenol]

A solution of the product from Example 8 (0.93 g, 2.06 mmol),hexamethyleneimine (0.51 mL, 4.53 mmol) and 37% aqueous formaldehyde(0.36 mL, 4.80 mmol) in 20 mL of ethanol was heated at 50° C. for 20hours under a nitrogen atmosphere. Additional 37% aqueous formaldehyde(0.18 mL, 2.40 mmol) and hexamethyleneimine (0.25 mL, 2.27 mmol) wereadded and the reaction mixture heated at 50° C. for an additional 48hours. The reaction mixture was cooled and concentrated. The residue wasdissolved in ethyl acetate (50 mL) and washed with water (20 mL) andsaturated aqueous NaCl solution. The organic phase was dried (MgSO₄),filtered, and concentrated. The residue was purified by chromatography(silica gel, 65% ethyl acetate/hexane) to give the title compound (0.23g, 17%) as an oil.

EXAMPLE 10 ##STR15##4,4'-[4-[Bis(phenylmethyl)amino]-1-methylbutylidene]-bis[2-[(hexahydro-1H-azepin-1yl)methyl]phenol]oxalic acid salt

A solution of the product from Example 9 (0.22 g, 0.33 mmol) in 5 mL Et₂O was treated with a solution of oxalic acid (0.13 g, 1.03 mmol) in 1 mLof ethanol. The resulting solution was triturated with 5 mL of Et₂ O andcollected by filtration. The solid collected was washed with Et₂ O anddried (P₂ O₅) under vacuum to give the title compound (0.28 g, 91%) as awhite solid, mp=111-148° C.

Analysis calculated for C₄₅ H₅₉ N₃ O₂.3.25 C₂ H₂ O₄ :

C, 64.00; H, 6.83; N, 4.35.

Found: C, 63.98; H, 6.79; N, 4.37.

EXAMPLE 11 ##STR16## 4,4'-(2-Aminoethylidene)bisphenol hydrochloride

According to the method of Kappe and Armstrong, (J. Org. Chem., 1964;29:826), a solution of octapamine hydrochloride (50 g, 0.264 mol) in 500mL of aqueous 6N HCl solution was treated with phenol (150 g, 1.59 mol)and the resulting mixture was heated at 100° C. for 48 hours. Thereaction mixture was cooled to room temperature and washed with ether.The aqueous phase was concentrated. The residue was dissolved in hotethanol, decolorized with charcoal, and filtered. The filtrate wastreated with ethyl acetate until the solution became slightly cloudy.The solid which formed on cooling was collected by filtration and driedto give the title compound (31.48 g, 0.120 mol) as a white solid,mp=27714 278° C.

Analysis calculated for C₁₄ H₁₅ NO₂.HCl:

C, 63.28; H, 6.07; N, 5.27; Cl, 13.34.

Found: C, 63.19; H, 6.18; N, 5.28; Cl, 13.32.

A second crop of the title compound (15.9 g, 0.060 mol) was obtained byconcentration of the filtrate followed by treatment of the residue withethanol and ethyl acetate.

EXAMPLE 12 ##STR17## (+/-)-4,4'-(2-Aminopropylidene)bisphenolhydrochloride

According to the method of Kappe and Armstrong (J. Org. Chem., 1964;29:826), a solution of (±)-α-(1-aminoethyl)-4-hydroxybenzyl alcoholhydrochloride (34.0 g, 0.361 mol) was dissolved in 200 mL of aqueous 6NHCl solution and treated with phenol (10.0 g, 49.1 mmol). The resultingmixture was heated at 100° C. for 6 hours. The reaction mixture wascooled to room temperature and washed with ether (3×50 mL). The aqueousphase was concentrated to give a solid (15.26 g). The solid obtained wassuspended in 100 mL of boiling ethanol. The resulting suspension wastreated with water (5 mL), and a solution was formed. The resultingsolution was treated with ethyl acetate until a persistent cloudinesswas obtained. The solid which formed on cooling was collected by suctionfiltration and dried to give the title compound (7.91 g, 58%) as a whitesolid, mp=>300° C.

Analysis calculated for C₁₅ H₁₇ NO₂.HCl:

C, 64.40; H, 6.49; N, 5.01; Cl, 12.67.

C, 64.45; H, 6.43; N, 5.03; Cl, 12.68.

EXAMPLE 13 ##STR18## N-[2,2-Bis-(4-hydroxyphenyl)ethyl]benzamide

A solution of the product from Example 11 (5.00 g, 18.8 mmol) wasdissolved in tetrahydrofuran (100 mL), dichloromethane (100 mL),saturated aqueous NaHCO₃ solution (50 mL), and water (50 mL). Theresulting mixture was treated with benzoyl chloride (3.3 mL, 28.2 mmol)and stirred for 4 days. The reaction mixture was extracted withchloroform (3×200 mL). The combined organic extracts were dried (MgSO₄),filtered, and concentrated to give the title compound (5.16 g, 82%) as awhite solid.

Analysis calculated for C₂₁ H₁₉ NO₃ :

C, 75.66; H, 5.74; N, 4.20.

Found: C, 75.32; H, 6.14; N, 3.99.

EXAMPLE 14 ##STR19##N-[2,2-Bis-(4-hydroxyphenyl)ethyl]-2,2-diphenylacetamide

A solution of the product from Example 11 (5.00 g, 18.8 mmol) wasdissolved in tetrahydrofuran (100 mL), dichloromthane (100 mL),saturated aqueous NaHCO₃ solution (50 mL), and water (50 mL). Theresulting mixture was treated with diphenylacetyl chloride (6.50 g, 28.2mmol). The reaction mixture was stirred at room temperature until nostarting material remained. The reaction mixture was extracted intodichloromethane. The combined organic extracts were dried (MgSO₄),filtered, and concentrated. The residue was recrystallized fromtetrahydrofuran/diisopropyl ether to give the title compound (5.57 g,70%) as a white solid.

EXAMPLE 15 ##STR20##N-[2,2-Bis-(4-hydroxyphenyl)-1-methylethyl]benzamide

The product from Example 12 (5.00 g, 17.0 mmol) was dissolved inchloroform (70 mL), THF (30 mL), and 50 mL saturated aqueous NaHCO₃solution. The reaction mixture was treated with benzoyl chloride (2.5mL, 21.5 mmol) and the water (25 mL). The reaction mixture was stirredfor 5 days. The organic phase was collected, dried (MgSO₄), andfiltered. The filtrate was concentrated. The residue obtained wasdissolved in hot THF and diisopropylether was added until a slightcloudiness developed. The solid which formed on cooling was collected byfiltration, washed with additional diisopropylether, and dried undervacuum to give the title compound (4.78 g, 77%) as a white solid.

EXAMPLE 16 ##STR21##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-benzamide

A solution of the product from Example 13 (2.00 g, 6.00 mmol) in 40 mLof ethanol was treated with hexamethyleneimine (1.25 g, 12.6 mmol) and37% aqueous formaldehyde solution (0.90 mL, 12.6 mmol). The resultingsolution was heated at reflux for 24 hours. Additionalhexamethyleneimine and 37% aqueous formaldehyde solution were added, andthe reaction mixture was heated until the starting material wasconsumed. The reaction mixture was cooled and concentrated. The residuewas purified by chromatography (silica gel, 10:1:0.1 EtOAc/EtOH/NH₄ OH)to give the product as a yellow solid (1.06 g, 32%).

EXAMPLE 17 ##STR22##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-2,2-diphenylacetamide

A solution of the product from Example 14 (2.00 g, 4.72 mmol) in 40 mLof ethanol was treated with hexamethyleneimine (0.98 g, 9.92 mmol) and37% aqueous formaldehyde solution (0.72 mL, 9.89 mmol). The resultingsolution was heated at reflux for 24 hours. Additionalhexamethyleneimine and 37% aqueous formaldehyde solution were added andthe reaction mixture was heated until the starting material wasconsumed. The reaction mixture was cooled and concentrated. The residuewas purified by chromatography (silica gel, 10:1 EtOAc/EtOH) to give theproduct as an oil (0.98 g, 32%).

EXAMPLE 18 ##STR23##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)-1-methylethyl]benzamide

A solution of the product from Example 13 (0.50 g, 1.44 mmol) in 20 mLof ethanol was treated with hexamethyleneimine (0.30 g, 3.02 mmol) and37% aqueous formaldehyde solution (0.21 mL, 2.74 mmol). The resultingsolution was heated at reflux for 24 hours. The reaction mixture wascooled and concentrated. The residue was broken up in diisopropyl etherto give the title compound (0.63 g, 81%) as a tan solid.

EXAMPLE 19 ##STR24##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-benzamide oxalicacid salt

A solution of the product from Example 16 (0.94 g, 1.79 mmol) and oxalicacid (0.26 g, 2.00 mmol) in 5 mL ethanol was triturated with ethylacetate. The solid which formed was collected by filtration and driedunder vacuum at 75° C. to give the title compound (0.875 g, 66%) as awhite solid.

Analysis calculated for C₃₅ H₄₅ N₃ O₃.2.00 C₂ H₂ O₄ :

C, 63.93; H, 6.75; N, 5.75.

Found: C, 63.94; H, 6.82; N, 5.84.

EXAMPLE 20 ##STR25##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-2,2-diphenylacetamideoxalic acid salt

A solution of the product from Example 17 (0.89 g, 1.22 mmol) and oxalicacid (0.34 g, 2.66 mmol) in 5 mL ethanol was triturated with isopropanol(20 mL). Ethyl acetate (30 mL) was added and the solid collected byfiltration. The solid was dried under vacuum at 75° C. to give the titlecompound (0.215 g, 20%) as a white solid.

Analysis calculated for C₄₅ H₄₅₁ N₃ O₃.2.5 C₂ H₂ O₄ :

C, 61.95; H, 6.59; N, 5.29.

Found: C, 62.06; H, 6.54; N, 5.57.

EXAMPLE 21 ##STR26##N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)-1-methylethyl]benzamideoxalic acid salt

a solution of the product from Example 18 (0.28 g, 0.49 mmol) and oxalicacid (0.13 g, 1.02 mmol) in 5 mL ethanol was triturated with ethylacetate. The solid which formed was collected by filtration and driedunder vacuum at 75° C. to give the title compound (0.097 g, 25%) as awhite solid.

Analysis calculated for C₃₆ H₄₇ N₃ O₃.2.5 C₂ H₂ O₄ :

C, 61.95; H, 6.59; N, 5.29.

Found: C, 62.06; H, 6.54; N, 5.57.

What is claimed is:
 1. A compound of formula ##STR27## or apharmaceutically acceptable salt thereof wherein: R¹ and R² are eachindependently hydrogen, alkyl, aryl or arylalkyl, or are taken togetherwith the nitrogen to which they are attached to form a ring of from 4 to8 carbon atoms;R⁸ and R⁹ are each independently hydrogen, alkyl, aryl orarylalkyl, or are taken together with the nitrogen to which they areattached to form a ring of from 4 to 8 carbon atoms; R³, R⁴, R⁵, R⁶, R⁷,R¹⁰, and R¹¹ are each independently hydrogen, alkyl, or halogen; X is--(CH₂)_(p) --,--(CH₂)_(p) CONR¹⁶ --, --(CR¹⁸ R¹⁹)_(p) NR¹⁶ CO--,wherein each R¹⁸ and R¹⁹ is each independently hydrogen or alkyl of from1 to 4, --(CH₂)_(p) NR¹⁶ --, --(CH₂)_(p) O--, --(CH₂)_(p) S--, wherein pis an integer of from 0 to 3 and R¹⁶ is hydrogen or simple alkyl; Y isNR¹² R¹³, CR¹⁷ R¹² R¹³, or aryl wherein R¹⁷ is hydrogen, hydroxy oralkyl; R¹² and R¹³ are each independently hydrogen, alkyl, substitutedaryl wherein the substituents are selected from simple alkyl, OH, OCH₃,NO₂, and NHCOCH₃, arylalkyl, heteroaryl, or heteroarylalkyl; n is aninteger of from 1 to 3; o is an integer of from 1 to 3; and m is aninteger of from 1 to 3; with the proviso that --X--(CH₂)_(m) --Y is notstraight or branched alkyl.
 2. A compound according to claim 1 whereinR³, R⁵, R¹¹, and R⁷ are hydrogen.
 3. A compound according to claim 1wherein R³, R⁵, R¹¹, and R⁷ are hydrogen and n is 1 and o is
 1. 4. Acompound according to claim 1 wherein R³, R⁵, R¹¹, and R⁷ are hydrogen,n is 1, o is 1, and X is --(CH₂)_(p) -- or ##STR28##
 5. A compoundselected from4,4'-(4-Hydroxy-1-methyl-4,4-diphenylbutylidene)-bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol],4,4'-(1-Methyl-4,4-diphenylbutylidene)bis[2-[(hexahydro-1H-azepin-1-yl)methyl]phenol],4,4'-[4-[Bis(phenylmethyl)amino]-1-methylbutylidene]bis[2-[(hexahydro-1H-azepin-1-yl)-ethyl]phenol],N-[2,2-Bis-(3-azepan-1-ylmthyl-4-hydroxyphenyl)ethyl]benzamide,N-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)ethyl]-2,2-diphenylacetamide,andN-[2,2-Bis-(3-azepan-1-ylmethyl-4-hydroxyphenyl)-1-methylethyl]benzamide.6. A method for treating disorders responsive to the blockade ofvoltage-gated calcium channels in a mammal in need of said treatmentwhich comprises administering to said mammal a therapeutically effectiveamount of a compound according to claim 1 in unit dosage form.
 7. Apharmaceutical composition comprising a therapeutically effective amountof one or more compounds according to claim 1 together with apharmaceutically acceptable carrier.
 8. A method of treating pain in amammal suffering therefrom comprising administering a compositionaccording to claim 7 to said mammal.
 9. A method of treating cerebralischemia in a mammal suffering therefrom comprising administering acomposition according to claim 7 to said mammal.